Abstract:

The present invention relates to aminopyrazine derivatives, compositions
and medicaments containing the same, as well as processes for the
preparation and use of such compounds, compositions and medicaments. Such
aminopyrazine derivatives are useful in the treatment of diseases
associated with inappropriate tyrosine and/or serine/threonine kinase
activity.

Claims:

1. A compound of the Formula (I): ##STR00071## or a salt thereof wherein:A
is thienyl;D is selected from the group consisting of: ##STR00072##
R2 is --H, halo, C1-C6alkyl, C1-C6alkoxy, aryl,
heteroaryl, --S(O)2NR4R5, --COOH, --C(O)OR6,
--C(O)NR4R5, NRR', --N(H)C(O)NRR', --N(H)C(O)R, or
--N(H)S(O)2R;q is 1, 2, 3, or 4;R3 is --H,
C1-C3alkyl, aryl, aralkyl, or heteroaryl;R4 is --H or
C1-C3 alkyl;R5 is --H or C1-C3 alkyl; orR4
and R5 together with the nitrogen to which they are attached form a
heterocyclyl ring, said ring optionally containing 1 or 2 additional
oxygen, S(O)m, or nitrogen atoms; said nitrogen atoms being
optionally substituted by a C1-C3 alkyl group;m is 0, 1, or 2;
andR6 is C1-C6alkyl.

2. A pharmaceutical composition comprising a therapeutically effective
amount of a compound of claim 1 and one or more of pharmaceutically
acceptable carriers, diluents and excipients.

3. The compound of claim 1, wherein D is: ##STR00073##

4. The compound of claim 1, wherein said compound is
3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-thien-2-ylpyrazin-2-amine; or
a salt, solvate, or physiologically functional derivative thereof.

Description:

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001]This application is a Divisional of U.S. application Ser. No.
10/549,972 filed on Sep. 20, 2005, now allowed; which is a U.S. National
Phase Application of International Patent Application No.
PCT/US2004/008301 filed on Mar. 18, 2004; which claims priority from U.S.
Provisional Application No. 60/456,872 filed on Mar. 21, 2003; all of
which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

[0002]The present invention relates to aminopyrazine derivatives,
compositions and medicaments containing the same, as well as processes
for the preparation and use of such compounds, compositions and
medicaments. Such aminopyrazine derivatives are useful in the treatment
of diseases associated with inappropriate tyrosine and/or
serine/threonine kinase activity.

BACKGROUND OF THE INVENTION

[0003]An important large family of enzymes is the protein kinase enzyme
family. Currently, there are about 400 different known protein kinases.
However, because three to four percent of the human genome is a code for
the formation of protein kinases, there may be many thousands of distinct
and separate kinases in the human body. Protein kinases serve to catalyze
the phosphorylation of an amino acid side chain in various proteins by
the transfer of the γ-phosphate of the ATP-Mg2+ complex to
said amino acid side chain. These enzymes control the majority of the
signaling processes inside cells, thereby governing cell function,
growth, differentiation and destruction (apoptosis) through reversible
phosphorylation of the hydroxyl groups of serine, threonine and tyrosine
residues in proteins. Studies have shown that protein kinases are key
regulators of many cell functions, including signal transduction,
transcriptional regulation, cell motility, and cell division. Several
oncogenes have also been shown to encode protein kinases, suggesting that
kinases play a role in oncogenesis. These processes are highly regulated,
often by complex intermeshed pathways where each kinase will itself be
regulated by one or more kinases. Consequently, aberrant or inappropriate
protein kinase activity can contribute to the rise of disease states
associated with such aberrant kinase activity. Due to their physiological
relevance, variety and ubiquitousness, protein kinases have become one of
the most important and widely studied family of enzymes in biochemical
and medical research.

[0004]The protein kinase family of enzymes is typically classified into
two main subfamilies: Protein Tyrosine Kinases and Protein
Serine/Threonine Kinases, based on the amino acid residue they
phosphorylate. The serine/threonine kinases (PSTK), includes cyclic AMP-
and cyclic GMP-dependent protein kinases, calcium- and
phospholipid-dependent protein kinase, calcium- and calmodulin-dependent
protein kinases, casein kinases, cell division cycle protein kinases and
others. These kinases are usually cytoplasmic or associated with the
particulate fractions of cells, possibly by anchoring proteins. Aberrant
protein serine/threonine kinase activity has been implicated or is
suspected in a number of pathologies such as rheumatoid arthritis,
psoriasis, septic shock, bone loss, many cancers and other proliferative
diseases. Accordingly, serine/threonine kinases and the signal
transduction pathways which they are part of are important targets for
drug design. The tyrosine kinases phosphorylate tyrosine residues.
Tyrosine kinases play an equally important role in cell regulation. These
kinases include several receptors for molecules such as growth factors
and hormones, including epidermal growth factor receptor, insulin
receptor, platelet derived growth factor receptor and others. Studies
have indicated that many tyrosine kinases are transmembrane proteins with
their receptor domains located on the outside of the cell and their
kinase domains on the inside. Much work is also under progress to
identify modulators of tyrosine kinases as well.

[0005]A major signal transduction systems utilized by cells is the
RhoA-signalling pathways. RhoA is a small GTP binding protein that can be
activated by several extracellular stimuli such as growth factor,
hormones, mechanic stress, osmotic change as well as high concentration
of metabolite like glucose. RhoA activation involves GTP binding,
conformation alteration, post-translational modification
(geranylgeranyllization and farnesylation) and activation of its
intrinsic GTPase activity. Activated RhoA is capable of interacting with
several effector proteins including ROCKs and transmit signals into
cellular cytoplasm and nucleus.

[0006]ROCK1 and 2 constitute a family of kinases that can be activated by
RhoA-GTP complex via physical association. Activated ROCKs phosphorylate
a number of substrates and play important roles in pivotal cellular
functions. The substrates for ROCKs include myosin binding subunit of
myosin light chain phosphatase (MBS, also named MYPT1), adducin, moesin,
myosin light chain (MLC), LIM kinase as well as transcription factor FHL.
The phosphorylation of theses substrates modulate the biological activity
of the proteins and thus provide a means to alter cell's response to
external stimuli. One well documented example is the participation of
ROCK in smooth muscle contraction. Upon stimulation by phenylephrine,
smooth muscle from blood vessels contracts. Studies have shown that
phenylephrine stimulates b-adrenergic receptors and leads to the
activation of RhoA. Activated RhoA in turn stimulates kinase activity of
ROCK1 and which in turn phosphorylates MBS. Such phosphorylation inhibits
the enzyme activity of myosin light chain phosphatase and increases the
phosphorylation of myosin light chain itself by a calcium-dependent
myosin light chain kinase (MLCK) and consequently increases the
contractility of myosin-actin bundle, leading to smooth muscle
contraction. This phenomena is also sometimes called calcium
sensitization. In addition to smooth muscle contraction, ROCKs have also
been shown to be involved in cellular functions including apoptosis, cell
migration, transcriptional activation, fibrosis, cytokinesis,
inflammation and cell proliferation. Moreover, in neurons ROCK plays a
critical role in the inhibition of axonal growth by myelin-associated
inhibitory factors such as myelin-associated glycoprotein (MAG).
ROCK-activity also mediates the collapse of growth cones in developing
neurons. Both processes are thought to be mediated by ROCK-induced
phosphorylation of substrates such as LIM kinase and myosin light chain
phosphatase, resulting in increased contractility of the neuronal
actin-myosin system.

[0007]Inhibitors of ROCKs have been suggested for use in the treatments of
a variety of diseases. They include cardiovascular diseases such as
hypertension, chronic and congestive heart failure, cardiac hypertrophy,
restenosis, chronic renal failure and atherosclerosis. In addition,
because of its muscle relaxing properties, it is also suitable for
asthma, male erectile dysfunctions, female sexual dysfunction and
over-active bladder syndrome. ROCK inhibitors have been shown to possess
anti-inflammatory properties. Thus they can be used as treatment for
neuroinflammatory diseases such as stroke, multiple sclerosis,
Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis
and inflammatory pain, as well as other inflammatory diseases such as
rheumatoid arthritis, irritable bowel syndrome, inflammatory bowel
disease. In addition, based on their neurite outgrowth inducing effects,
ROCK inhibitors could be useful drugs for neuronal regeneration, inducing
new axonal growth and axonal rewiring across lesions within the CNS. ROCK
inhibitors are therefore likely to be useful for regenerative (recovery)
treatment of CNS disorders such as spinal cord injury, acute neuronal
injury (stroke, traumatic brain injury), Parkinson's disease, Alzheimer's
disease and other neurodegenerative disorders. Since ROCK inhibitors
reduce cell proliferation and cell migration, they could be useful in
treating cancer and tumor metastasis. Further more, there is evidence
suggesting that ROCK inhibitors suppress cytoskeletal rearrangement upon
virus invasion, thus they also have potential therapeutic value in
anti-viral and anti-bacterial applications. ROCK inhibitors are also
useful for the treatment of insulin resistance and diabetes.

[0008]The present inventors have discovered novel amino-pyrazine
compounds, which are inhibitors of ROCK activity. Such derivatives are
useful in the treatment of disorders associated with inappropriate ROCK
activity.

SUMMARY OF THE INVENTION

[0009]In one aspect of the present invention, there is provided a compound
of Formula (I):

##STR00001##

or a salt, solvate, or physiologically functional derivative
thereof:wherein:A is aryl, heteroaryl, C1-C6alkenyl,
C1-C6alkynyl, --CN, halo, --COOH, --C(O)NR4R5,
--NRR', --N(R')S(O)2R, --N(R')C(O)R, or --N(R')C(O)NR4R5;R
is --H, C1-C6 alkyl, aryl, or heteroaryl;R' is --H or
C1-C3 alkyl;D is selected from the group:

##STR00002##

R2 is --H, halo, C1-C6alkyl, C1-C6alkoxy, aryl,
heteroaryl, --S(O)2NR4R5, --COOH, --C(O)OR6,
--C(O)NR4R5, NRR', --N(H)C(O)NRR', --N(H)C(O)R, or
--N(H)S(O)2R;q is 1, 2, 3, or 4;R3 is --H,
C1-C3alkyl, aryl, aralkyl, or heteroaryl;R4 is --H or
C1-C3 alkyl;R5 is --H or C1-C3 alkyl; orR4
and R5 together with the nitrogen to which they are attached form a
heterocyclyl ring, said ring optionally containing 1 or 2 additional
oxygen, S(O)m, or nitrogen atoms; said nitrogen atoms being
optionally substituted by a C1-C3 alkyl group;m is 0, 1, or 2;
andR6 is C1-C6alkyl.

[0010]In a second aspect of the present invention, there is provided a
compound of Formula (I):

R2 is --H, halo, C1-C6 alkyl, C1-C6 alkoxy,
heteroaryl, --S(O)2NR4R5, --COOH, --C(O)OR6, or
--C(O)NR4R5, NRR', --N(H)C(O)NRR', --N(H)C(O)R, or
--N(H)S(O)2R;q is 1, 2, 3, or 4;R3 is --H,
C1-C3alkyl, aryl, aralkyl, or heteroaryl;R4 is --H or
C1-C3 alkyl;R5 is --H or C1-C3 alkyl; orR4
and R5 together with the nitrogen to which they are attached form a
heterocyclyl ring, said ring optionally containing 1 or 2 additional
oxygen, S(O)m, or nitrogen atoms; said nitrogen atoms being
optionally substituted by a C1-C3 alkyl group;m is 0, 1, or 2;
andR6 is C1-C6 alkyl.

[0011]In third aspect of the present invention, there is provided a
compound of Formula (I):

##STR00005##

or a salt, solvate, or physiologically functional derivative
thereof:wherein:A is aryl optionally substituted with at least one
R1 group or heteroaryl optionally substituted with at least one
R1 group;R is --H, C1-C6 alkyl, aryl, or heteroaryl;R' is
--H or C1-C3 alkyl;R1 is C1-C6alkyl, aryl,
C1-C6alkoxy, aryloxy, halo, --COOH, --CN,
--S(O)2NR4R5, --S(O)2R, --C(O)NR4R5,
--NRR', --N(H)C(O)NR4R5, --O(CH2)nCOOH,
--(CH2)nCOOH, --C(O)O(CH2)nR,
--(CH2)nN(H)C(O)OR, or --N(R')S(O)2R;D is selected from
the group:

##STR00006##

R2 is --H, halo, C1-C6 alkyl, C1-C6 alkoxy,
heteroaryl, --S(O)2NR4R5, --COOH, --C(O)OR, or
--C(O)NR4R5, NRR', --N(H)C(O)NRR', --N(H)C(O)R, or
--N(H)S(O)2R;q is 1, 2, 3, or 4;R3 is --H,
C1-C3alkyl, aryl, aralkyl, or heteroaryl;R4 is --H or
C1-C3 alkyl;R5 is --H or C1-C3alkyl; orR4
and R5 together with the nitrogen to which they are attached form a
heterocyclyl ring, said ring optionally containing 1 or 2 additional
oxygen, S(O)m, or nitrogen atoms; said nitrogen atoms being
optionally substituted by a C1-C3 alkyl group;m is 0, 1, or 2;
andR6 is C1-C6alkyl.

[0012]In a fourth aspect of the present invention, there is provided a
compound of Formula (I):

##STR00007##

or a salt, solvate, or physiologically functional derivative
thereof:wherein:A is C1-C6 alkenyl or C1-C6 alkynyl;R
is --H, C1-C6 alkyl, aryl, or heteroaryl;R' is --H or
C1-C3 alkyl;D is selected from the group:

##STR00008##

R2 is --H, halo, C1-C6 alkyl, C1-C6 alkoxy,
heteroaryl, --S(O)2NR4R5, --COOH, --C(O)OR6, or
--C(O)NR4R5, NRR', --N(H)C(O)NRR', --N(H)C(O)R, or
--N(H)S(O)2R;q is 1, 2, 3, or 4;R3 is --H,
C1-C3alkyl, aryl, aralkyl, or heteroaryl;R4 is --H or
C1-C3 alkyl;R5 is --H or C1-C3 alkyl; orR4
and R5 together with the nitrogen to which they are attached form a
heterocyclyl ring, said ring optionally containing 1 or 2 additional
oxygen, S(O)m, or nitrogen atoms; said nitrogen atoms being
optionally substituted by a C1-C3 alkyl group;m is 0, 1, or 2;
andR6 is C1-C6 alkyl.

[0013]In a fifth aspect of the present invention, there is provided a
compound of Formula (I):

##STR00009##

or a salt, solvate, or physiologically functional derivative
thereof:wherein:

A is --CN, --COOH, or --C(O)NR4R5;

[0014]R is --H, C1-C6 alkyl, aryl, or heteroaryl;R' is --H or
C1-C3 alkyl;D is selected from the group:

##STR00010##

R2 is --H, halo, C1-C6 alkyl, --COOH, C1-C6
alkoxy, heteroaryl, --S(O)2NR4R5, --C(O)OR6, or
--C(O)NR4R5, NRR', --N(H)C(O)NRR', --N(H)C(O)R, or
--N(H)S(O)2R;q is 1, 2, 3, or 4;R3 is --H,
C1-C3alkyl, aryl, aralkyl, or heteroaryl;R4 is --H or
C1-C3 alkyl;R5 is --H or C1-C3 alkyl; orR4
and R5 together with the nitrogen to which they are attached form a
heterocyclyl ring, said ring optionally containing 1 or 2 additional
oxygen, S(O)m, or nitrogen atoms; said nitrogen atoms being
optionally substituted by a C1-C3 alkyl group;m is 0, 1, or 2;
andR6 is C1-C6 alkyl.

[0015]In a sixth aspect of the present invention, there is provided a
compound of Formula (I):

##STR00011##

or a salt, solvate, or physiologically functional derivative
thereof:wherein:

A is --NRR', --N(R')S(O)2R, --N(R')C(O)R, or
--N(R')C(O)NR4R5;

[0016]R is --H, C1-C6 alkyl, aryl, or heteroaryl;R' is --H or
C1-C3 alkyl;D is selected from the group:

##STR00012##

R2 is --H, halo, C1-C6 alkyl, C1-C6 alkoxy,
heteroaryl, --S(O)2NR4R5, --COOH, --C(O)OR, or
--C(O)NR4R5, NRR', --N(H)C(O)NRR', --N(H)C(O)R, or
--N(H)S(O)2R;q is 1, 2, 3, or 4;R3 is --H,
C1-C3alkyl, aryl, aralkyl, or heteroaryl;R4 is --H or
C1-C3 alkyl;R5 is --H or C1-C3alkyl; orR4
and R5 together with the nitrogen to which they are attached form a
heterocyclyl ring, said ring optionally containing 1 or 2 additional
oxygen, S(O)m, or nitrogen atoms; said nitrogen atoms being
optionally substituted by a C1-C3 alkyl group;m is 0, 1, or 2;
andR6 is C1-C6alkyl.

[0017]In a seventh aspect of the present invention, there is provided a
pharmaceutical composition comprising a therapeutically effective amount
of a compound of formula (I) or a salt, solvate, or a physiologically
functional derivative thereof and one or more of pharmaceutically
acceptable carriers, diluents and excipients.

[0018]In an eighth aspect of the present invention, there is provided a
method of treating a disorder in a mammal, said disorder being mediated
by inappropriate ROCK-1 activity, comprising: administering to said
mammal a therapeutically effective amount of a compound of formula (I) or
a salt, solvate or a physiologically functional derivative thereof.

[0019]In a ninth aspect of the present invention, there is provided a
compound of formula (I), or a salt, solvate, or a physiologically
functional derivative thereof for use in therapy.

[0020]In a tenth aspect of the present invention, there is provided the
use of a compound of formula (I), or a salt, solvate, or a
physiologically functional derivative thereof in the preparation of a
medicament for use in the treatment of a disorder mediated by
inappropriate ROCK-1 activity.

DETAILED DESCRIPTION OF THE INVENTION

[0021]As used herein, the term "effective amount" means that amount of a
drug or pharmaceutical agent that will elicit the biological or medical
response of a tissue, system, animal or human that is being sought, for
instance, by a researcher or clinician. Furthermore, the term
"therapeutically effective amount" means any amount which, as compared to
a corresponding subject who has not received such amount, results in
improved treatment, healing, prevention, or amelioration of a disease,
disorder, or side effect, or a decrease in the rate of advancement of a
disease or disorder. The term also includes within its scope amounts
effective to enhance normal physiological function.

[0023]As used herein, the terms "C1-C3 alkyl" and
"C1-C6 alkyl" refer to an alkyl group, as defined above,
containing at least 1, and at most 3 or 6 carbon atoms respectively.
Examples of such branched or straight-chained alkyl groups useful in the
present invention include, but are not limited to, methyl, ethyl,
n-propyl, isopropyl, isobutyl, n-butyl, t-butyl, n-pentyl, isopentyl, and
n-hexyl.

[0024]As used herein, the term "alkylene" refers to a straight or branched
chain divalent hydrocarbon radical having from one to ten carbon atoms,
optionally substituted with substituents selected from the group which
includes C1-C6 alkyl, C1-C6 alkoxy, C1-C6
alkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6
alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by
alkyl, carboxy, carbamoyl optionally substituted by alkyl, aryl,
heteroaryl, heterocyclyl, aminosulfonyl optionally substituted by alkyl,
nitro, cyano, halo, and C1-C6 perfluoroalkyl, multiple degrees
of substitution being allowed. Examples of "alkylene" as used herein
include, but are not limited to, methylene, ethylene, n-propylene,
n-butylene, and the like.

[0025]As used herein, the term "C1-C3 alkylene" refers to an
alkylene group, as defined above, which contains at least 1, and at most
3 or 6, carbon atoms respectively. Examples of "C1-C6 alkylene"
and "C1-C6 alkylene" groups useful in the present invention
include, but are not limited to, methylene, ethylene, n-propylene,
n-butylene, isopentylene, and the like.

[0026]As used herein, the term "halogen" refers to fluorine (F), chlorine
(Cl), bromine (Br), or iodine (I) and the term "halo" refers to the
halogen radicals: fluoro (--F), chloro (--Cl), bromo (--Br), and iodo
(--I).

[0027]As used herein, the term "C1-C6 haloalkyl" refers to an
alkyl group as defined above containing at least 1, and at most 6 carbon
atoms respectively substituted with at least one halo group, halo being
as defined herein. Examples of such branched or straight chained
haloalkyl groups useful in the present invention include, but are not
limited to, methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl
substituted independently with one or more halos, e.g., fluoro, chloro,
bromo and iodo.

[0028]As used herein, the term "cycloalkyl" refers to a non-aromatic
cyclic hydrocarbon ring containing from 3 to 10 carbon atoms and which
optionally includes a C1-C6 alkyl linker through which it may
be attached. In a like manner the term "C3-C7 cycloalkyl"
refers to a non-aromatic cyclic hydrocarbon ring having from three to
seven carbon atoms and which optionally includes a C1-C6 alkyl
linker through which it may be attached. The C1-C6 alkyl group
is as defined above. Exemplary "C3-C7 cycloalkyl" groups useful
in the present invention include, but are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0029]As used herein, the term "heterocyclic" or the term "heterocyclyl"
refers to a three to twelve-membered non-aromatic heterocyclic ring,
being saturated or having one or more degrees of unsaturation, containing
one or more heteroatom substitutions selected from S, S(O), S(O)2,
O, or N, optionally substituted with substituents selected from the group
consisting of C1-C6 alkyl, C1-C6 alkoxy,
C1-C6 alkylsulfanyl, C1-C6 alkylsulfenyl,
C1-C6 alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally
substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl,
aminosulfonyl optionally substituted by alkyl, nitro, cyano, halo, aryl,
aralkyl, heteroaryl, or C1-C6 perfluoroalkyl, multiple degrees
of substitution being allowed. Such a ring may be optionally fused to one
or more other "heterocyclic" ring(s) or cycloalkyl ring(s). Examples of
"heterocyclic" moieties include, but are not limited to, tetrahydrofuran,
pyran, 1,4-dioxane, 1,3-dioxane, piperidine, piperazine,
2,4-piperazinedione, pyrrolidine, imidazolidine, pyrazolidine,
morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, and
the like.

[0031]As used herein, the term "aralkyl" refers to an aryl or heteroaryl
group, as defined herein, attached through a C1-C3 alkylene
linker, wherein the C1-C3 alkylene is as defined herein.
Examples of "aralkyl" include, but are not limited to, benzyl,
phenylpropyl, 2-pyridylmethyl, 3-isoxazolylmethyl,
5-methyl-3-isoxazolylmethyl, and 2-imidazolyl ethyl.

[0033]As used herein, the term "alkoxy" refers to the group RaO--,
where Ra is alkyl as defined above and the terms "C1-C3
alkoxy" and "C1-C6 alkoxy" refer to an alkoxy group as defined
herein wherein the alkyl moiety contains at least 1, and at most 3 or 6,
carbon atoms. Exemplary "C1-C3 alkoxy" and "C1-C6
alkoxy" groups useful in the present invention include, but are not
limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and
t-butoxy.

[0034]As used herein, the term "amino" refers to the group --NH2.

[0035]As used herein the term "alkylamino" refers to the group --NHRa
wherein Ra is alkyl as defined above.

[0036]As used herein the term "arylamino" refers to the group --NHRa
wherein Ra is aryl as defined above.

[0037]As used herein the term "aralkylamino" refers to the group
--NHRa wherein Ra is an aralkyl group as defined above.

[0038]As used herein the term "aralkoxy" refers to the group
RbRaO--, where Ra is alkylene and Rb is aryl or
heteroaryl all as defined above.

[0039]As used herein the term "aryloxy" refers to the group RaO--,
where Ra is aryl or heteroaryl both as defined above.

[0040]As used herein the term "ureido" refers to the group
--NHC(O)NH2

[0041]As used herein, the term "arylurea" refers to the group
--NHC(O)NHRaRb wherein Ra is aryl or heteroaryl and
Rb is --H, alkyl, or aryl as defined above.

[0042]As used herein, the term "arylthiourea" refers to the group
--NHC(S)NHRa wherein Ra is aryl as defined above.

[0043]As used herein, the term "alkylurea" refers to the group
--NHC(O)NRaRb wherein Ra is alkyl and Rb is --H or
alkyl as defined above.

[0044]As used herein, the term "cycloalkylurea" refers to the group
--NHC(O)NHRa wherein Ra is cycloalkyl as defined above.

[0045]As used herein, the term "C3-C7 cycloalkoxy" refers to the
group RaO--, where Ra is C3-C7 cycloalkyl as defined
above. Exemplary C3-C7 cycloalkoxy groups useful in the present
invention include, but are not limited to, cyclobutoxy, and cyclopentoxy.

[0046]As used herein, the term "haloalkoxy" refers to the group
RaO--, where Ra is haloalkyl as defined above and the term
"C1-C6 haloalkoxy" refers to a haloalkoxy group as defined
herein wherein the haloalkyl moiety contains at least 1, and at most 6,
carbon atoms. Exemplary C1-C6 haloalkoxy groups useful in the
present invention include, but are not limited to, trifluoromethoxy.

[0047]As used herein, the term "alkylsulfanyl" refers to the group
RaS--, where Ra is alkyl as defined above and the term
"C1-C6 alkylsulfanyl" refers to an alkylsulfanyl group as
defined herein wherein the alkyl moiety contains at least 1, and at most
6, carbon atoms.

[0048]As used herein, the term "haloalkylsulfanyl" refers to the group
RaS--, where Ra is haloalkyl as defined above and the term
"C1-C6 haloalkylsulfanyl" refers to a haloalkylsulfanyl group
as defined herein wherein the alkyl moiety contains at least 1, and at
most 6, carbon atoms.

[0049]As used herein, the term "alkylsulfenyl" refers to the group
RaS(O)--, where Ra is alkyl as defined above and the term
"C1-C6 alkylsulfenyl" refers to an alkylsulfenyl group as
defined herein wherein the alkyl moiety contains at least 1, and at most
6, carbon atoms.

[0050]As used herein, the term "alkylsulfonyl" refers to the group
RaS(O)2--, where Ra is alkyl as defined above and the term
"C1-C6 alkylsulfonyl" refers to an alkylsulfonyl group as
defined herein wherein the alkyl moiety contains at least 1, and at most
6, carbon atoms.

[0051]As used herein, the term "alkylsulfonylamino" refers to the group
--NRbS(O)2Ra wherein Ra is alkyl and Rb is --H
or C1-C6alkyl as defined above, and the term "C1-C6
alkylsulfonylamino" refers to an alkylsulfonylamino group as defined
herein wherein the alkyl moiety contains at least 1, and at most 6,
carbon atoms.

[0052]As used herein, the term "arylsulfonylamino" refers to the group
--NRbS(O)2Ra wherein Ra is aryl or heteroaryl and
Rb is --H or C1-C6 alkyl as defined above.

[0053]As used herein, the term "alkylcarboxyamide" refers to the group
--NHC(O)Ra wherein Ra is alkyl, amino, or amino substituted
with alkyl, aryl or heteroaryl as described above.

[0054]As used herein the term "alkylcarboxy" refers to the group
--C(O)Ra wherein Ra is alkyl as described above.

[0055]As used herein, the term "oxo" refers to the group ═O.

[0056]As used herein, the term "mercapto" refers to the group --SH.

[0057]As used herein, the term "carboxy" refers to the group
--C(O)ORa, wherein Ra is H or alkyl as defined herein.

[0058]As used herein, the term "cyano" refers to the group --CN.

[0059]As used herein the term "cyanoalkyl" refers to the group --RaCN
wherein Ra is alkyl as defined above. Exemplary "cyanoalkyl" groups
useful in the present invention include, but are not limited to,
cyanomethyl, cyanoethyl, and cyanoisopropyl.

[0060]As used herein, the term "aminosulfonyl" refers to the group
--S(O)2RaRb wherein Ra and Rb are independently
H, C1-C6alkyl, aryl, aralkyl, or heteroaryl.

[0061]As used herein, the term "carbamoyl" refers to the group
--OC(O)NHRa where Ra is hydrogen or alkyl as defined herein.

[0062]As used herein, the term "carboxamide" refers to the group
--C(O)NRaRb wherein Ra and Rb are independently H,
C1-C6alkyl, aryl, aralkyl, or heteroaryl.

[0063]As used herein, the term "sulfanyl" shall refer to the group --S--.

[0064]As used herein, the term "sulfenyl" shall refer to the group
--S(O)--.

[0065]As used herein, the term "sulfonyl" shall refer to the group
--S(O)2-- or --SO2--.

[0066]As used herein, the term "acyl" refers to the group RaC(O)--,
where Ra is alkyl, cycloalkyl, or heterocyclyl as defined herein.

[0067]As used herein, the term "aroyl" refers to the group RaC(O)--,
where Ra is aryl as defined herein.

[0068]As used herein, the term "aroylamino" refers to the group
RaC(O)NH--, where Ra is aryl as defined herein.

[0069]As used herein, the term "heteroaroyl" refers to the group
RaC(O)--, where Ra is heteroaryl as defined herein.

[0070]As used herein, the term "alkoxycarbonyl" refers to the group
RaOC(O)--, where Ra is alkyl as defined herein.

[0071]As used herein, the term "acyloxy" refers to the group
RaC(O)O--, where Ra is alkyl, cycloalkyl, or heterocyclyl as
defined herein.

[0072]As used herein, the term "aroyloxy" refers to the group
RaC(O)O--, where Ra is aryl as defined herein.

[0073]As used herein, the term "heteroaroyloxy" refers to the group
RaC(O)O--, where Ra is heteroaryl as defined herein.

[0074]As used herein, the term "optionally" means that the subsequently
described event(s) may or may not occur, and includes both event(s),
which occur, and events that do not occur.

[0075]As used herein, the term "physiologically functional derivative"
refers to any pharmaceutically acceptable derivative of a compound of the
present invention, for example, an ester or an amide, which upon
administration to a mammal is capable of providing (directly or
indirectly) a compound of the present invention or an active metabolite
thereof. Such derivatives are clear to those skilled in the art, without
undue experimentation, and with reference to the teaching of Burger's
Medicinal Chemistry and Drug Discovery, 5th Edition, Vol. 1:
Principles and Practice, which is incorporated herein by reference to the
extent that it teaches physiologically functional derivatives.

[0076]As used herein, the term "solvate" refers to a complex of variable
stoichiometry formed by a solute (in this invention, a compound of
formula (I) or a salt or physiologically functional derivative thereof)
and a solvent. Such solvents for the purpose of the invention may not
interfere with the biological activity of the solute. Examples of
suitable solvents include, but are not limited to, water, methanol,
ethanol and acetic acid. Preferably the solvent used is a
pharmaceutically acceptable solvent. Examples of suitable
pharmaceutically acceptable solvents include, without limitation, water,
ethanol and acetic acid. Most preferably the solvent used is water.

[0077]As used herein, the term "substituted" refers to substitution with
the named substituent or substituents, multiple degrees of substitution
being allowed unless otherwise stated.

[0078]Certain of the compounds described herein may contain one or more
chiral atoms, or may otherwise be capable of existing as two enantiomers.
The compounds of this invention include mixtures of enantiomers as well
as purified enantiomers or enantiomerically enriched mixtures. Also
included within the scope of the invention are the individual isomers of
the compounds represented by formula (I) above as well as any wholly or
partially equilibrated mixtures thereof. The present invention also
covers the individual isomers of the compounds represented by the
formulas above as mixtures with isomers thereof in which one or more
chiral centers are inverted. Also, it is understood that any tautomers
and mixtures of tautomers of the compounds of formula (I) are included
within the scope of the compounds of formula (I).

[0079]It is to be understood that reference to compounds of formula (I)
above, following herein, refers to compounds within the scope of formula
(I) as defined above with respect to A, D, q, m, n, R, R', R1,
R2, R3, R4, R5, and R6 unless specifically
limited otherwise.

[0080]As recited above, various substituents, such as A, may be aryl or
heteroaryl. It is understood that such aryl or heteroaryl groups may be
substituted as indicated above in the definitions for "aryl" and
"heteroaryl". Alternatively, the aryl or heteroaryl groups may be
substituted by at least one R1, wherein R1 is as defined above.

[0081]In one embodiment, A is aryl or heteroaryl each optionally
substituted with at least one group R1. In one embodiment, A is aryl
optionally substituted with at least one group R1, preferably, A is
phenyl or phenyl substituted by at least one R1, more preferably A
is phenyl substituted by at least one R1. In another embodiment, A
is heteroaryl optionally substituted with at least one group R1.
Wherein R1 is as defined above.

[0082]In one embodiment, A is C1-C6alkenyl or
C1-C6alkynyl. In another embodiment, A is --CN, --COOH, or
--C(O)NR4R5. In a further embodiment, A is --NRR',
--N(R')S(O)2R, --N(R')C(O)R, or --N(R')C(O)NR4R5. Wherein
R, R1, R4 and R5 are as defined above.

[0122]While it is possible that, for use in therapy, therapeutically
effective amounts of a compound of formula (I), as well as salts,
solvates and physiological functional derivatives thereof, may be
administered as the raw chemical, it is possible to present the active
ingredient as a pharmaceutical composition. Accordingly, the invention
further provides pharmaceutical compositions, which include
therapeutically effective amounts of compounds of the formula (I) and
salts, solvates and physiological functional derivatives thereof, and one
or more pharmaceutically acceptable carriers, diluents, or excipients.
The compounds of the formula (I) and salts, solvates and physiological
functional derivatives thereof, are as described above. The carrier(s),
diluent(s) or excipient(s) must be acceptable in the sense of being
compatible with the other ingredients of the formulation and not
deleterious to the recipient thereof. In accordance with another aspect
of the invention there is also provided a process for the preparation of
a pharmaceutical formulation including admixing a compound of the formula
(I), or salts, solvates and physiological functional derivatives thereof,
with one or more pharmaceutically acceptable carriers, diluents or
excipients.

[0123]Pharmaceutical formulations may be presented in unit dose forms
containing a predetermined amount of active ingredient per unit dose.
Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to
700 mg, more preferably 5 mg to 100 mg of a compound of the formula (I),
depending on the condition being treated, the route of administration and
the age, weight and condition of the patient, or pharmaceutical
formulations may be presented in unit dose forms containing a
predetermined amount of active ingredient per unit dose. Preferred unit
dosage formulations are those containing a daily dose or sub-dose, as
herein above recited, or an appropriate fraction thereof, of an active
ingredient. Furthermore, such pharmaceutical formulations may be prepared
by any of the methods well known in the pharmacy art.

[0124]Pharmaceutical formulations may be adapted for administration by any
appropriate route, for example by the oral (including buccal or
sublingual), rectal, nasal, topical (including buccal, sublingual or
transdermal), vaginal or parenteral (including subcutaneous,
intramuscular, intravenous or intradermal) route. Such formulations may
be prepared by any method known in the art of pharmacy, for example by
bringing into association the active ingredient with the carrier(s) or
excipient(s).

[0125]Pharmaceutical formulations adapted for oral administration may be
presented as discrete units such as capsules or tablets; powders or
granules; solutions or suspensions in aqueous or non-aqueous liquids;
edible foams or whips; or oil-in-water liquid emulsions or water-in-oil
liquid emulsions.

[0126]For instance, for oral administration in the form of a tablet or
capsule, the active drug component can be combined with an oral,
non-toxic pharmaceutically acceptable inert carrier such as ethanol,
glycerol, water and the like. Powders are prepared by comminuting the
compound to a suitable fine size and mixing with a similarly comminuted
pharmaceutical carrier such as an edible carbohydrate, as, for example,
starch or mannitol. Flavoring, preservative, dispersing and coloring
agent can also be present.

[0127]Capsules are made by preparing a powder mixture, as described above,
and filling formed gelatin sheaths. Glidants and lubricants such as
colloidal silica, talc, magnesium stearate, calcium stearate or solid
polyethylene glycol can be added to the powder mixture before the filling
operation. A disintegrating or solubilizing agent such as agar-agar,
calcium carbonate or sodium carbonate can also be added to improve the
availability of the medicament when the capsule is ingested.

[0128]Moreover, when desired or necessary, suitable binders, lubricants,
disintegrating agents and coloring agents can also be incorporated into
the mixture. Suitable binders include starch, gelatin, natural sugars
such as glucose or beta-lactose, corn sweeteners, natural and synthetic
gums such as acacia, tragacanth or sodium alginate,
carboxymethylcellulose, polyethylene glycol, waxes and the like.
Lubricants used in these dosage forms include sodium oleate, sodium
stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium
chloride and the like. Disintegrators include, without limitation,
starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
Tablets are formulated, for example, by preparing a powder mixture,
granulating or slugging, adding a lubricant and disintegrant and pressing
into tablets. A powder mixture is prepared by mixing the compound,
suitably comminuted, with a diluent or base as described above, and
optionally, with a binder such as carboxymethylcellulose, an aliginate,
gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin,
a resorption accelerator such as a quaternary salt and/or an absorption
agent such as bentonite, kaolin or dicalcium phosphate. The powder
mixture can be granulated by wetting with a binder such as syrup, starch
paste, acadia mucilage or solutions of cellulosic or polymeric materials
and forcing through a screen. As an alternative to granulating, the
powder mixture can be run through the tablet machine and the result is
imperfectly formed slugs broken into granules. The granules can be
lubricated to prevent sticking to the tablet forming dies by means of the
addition of stearic acid, a stearate salt, talc or mineral oil. The
lubricated mixture is then compressed into tablets. The compounds of the
present invention can also be combined with a free flowing inert carrier
and compressed into tablets directly without going through the
granulating or slugging steps. A clear or opaque protective coating
consisting of a sealing coat of shellac, a coating of sugar or polymeric
material and a polish coating of wax can be provided. Dyestuffs can be
added to these coatings to distinguish different unit dosages.

[0129]Oral fluids such as solution, syrups and elixirs can be prepared in
dosage unit form so that a given quantity contains a predetermined amount
of the compound. Syrups can be prepared by dissolving the compound in a
suitably flavored aqueous solution, while elixirs are prepared through
the use of a non-toxic alcoholic vehicle. Suspensions can be formulated
by dispersing the compound in a non-toxic vehicle. Solubilizers and
emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene
sorbitol ethers, preservatives, flavor additive such as peppermint oil or
natural sweeteners or saccharin or other artificial sweeteners, and the
like can also be added.

[0130]Where appropriate, dosage unit formulations for oral administration
can be microencapsulated. The formulation can also be prepared to prolong
or sustain the release as for example by coating or embedding particulate
material in polymers, wax or the like.

[0131]The compounds of formula (I), and salts, solvates and physiological
functional derivatives thereof, can also be administered in the form of
liposome delivery systems, such as small unilamellar vesicles, large
unilamellar vesicles and multilamellar vesicles. Liposomes can be formed
from a variety of phospholipids, such as cholesterol, stearylamine or
phosphatidylcholines.

The compounds of formula (I) and salts, solvates and physiological
functional derivatives thereof may also be delivered by the use of
monoclonal antibodies as individual carriers to which the compound
molecules are coupled. The compounds may also be coupled with soluble
polymers as targetable drug carriers. Such polymers can include
polyvinylpyrrolidone, pyran copolymer,
polyhydroxypropylmethacrylamide-phenol,
polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine
substituted with palmitoyl residues. Furthermore, the compounds may be
coupled to a class of biodegradable polymers useful in achieving
controlled release of a drug, for example, polylactic acid, polyepsilon
caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,
polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic
block copolymers of hydrogels.

[0132]Pharmaceutical formulations adapted for transdermal administration
may be presented as discrete patches intended to remain in intimate
contact with the epidermis of the recipient for a prolonged period of
time. For example, the active ingredient may be delivered from the patch
by iontophoresis as generally described in Pharmaceutical Research, 3(6),
318 (1986).

[0134]For treatments of the eye or other external tissues, for example
mouth and skin, the formulations are preferably applied as a topical
ointment or cream. When formulated in an ointment, the active ingredient
may be employed with either a paraffinic or a water-miscible ointment
base. Alternatively, the active ingredient may be formulated in a cream
with an oil-in-water cream base or a water-in-oil base.

[0135]Pharmaceutical formulations adapted for topical administrations to
the eye include eye drops wherein the active ingredient is dissolved or
suspended in a suitable carrier, especially an aqueous solvent.

[0136]Pharmaceutical formulations adapted for topical administration in
the mouth include lozenges, pastilles and mouth washes.

[0137]Pharmaceutical formulations adapted for rectal administration may be
presented as suppositories or as enemas.

[0138]Pharmaceutical formulations adapted for nasal administration wherein
the carrier is a solid include a coarse powder having a particle size for
example in the range 20 to 500 microns which is administered in the
manner in which snuff is taken, i.e. by rapid inhalation through the
nasal passage from a container of the powder held close up to the nose.
Suitable formulations wherein the carrier is a liquid, for administration
as a nasal spray or as nasal drops, include aqueous or oil solutions of
the active ingredient.

[0139]Pharmaceutical formulations adapted for administration by inhalation
include fine particle dusts or mists, which may be generated by means of
various types of metered, dose pressurised aerosols, nebulizers or
insufflators.

[0141]Pharmaceutical formulations adapted for parenteral administration
include aqueous and non-aqueous sterile injection solutions which may
contain anti-oxidants, buffers, bacteriostats and solutes which render
the formulation isotonic with the blood of the intended recipient; and
aqueous and non-aqueous sterile suspensions which may include suspending
agents and thickening agents. The formulations may be presented in
unit-dose or multi-dose containers, for example sealed ampoules and
vials, and may be stored in a freeze-dried (lyophilized) condition
requiring only the addition of the sterile liquid carrier, for example
water for injections, immediately prior to use. Extemporaneous injection
solutions and suspensions may be prepared from sterile powders, granules
and tablets.

[0142]It should be understood that in addition to the ingredients
particularly mentioned above, the formulations may include other agents
conventional in the art having regard to the type of formulation in
question, for example those suitable for oral administration may include
flavouring agents.

[0143]A therapeutically effective amount of a compound of the present
invention will depend upon a number of factors including, for example,
the age and weight of the human or other animal, the precise condition
requiring treatment and its severity, the nature of the formulation, and
the route of administration, and will ultimately be at the discretion of
the attendant physician or veterinarian. However, an effective amount of
a compound of formula (I) for the treatment of neoplastic growth, for
example colon or breast carcinoma, will generally be in the range of 0.1
to 100 mg/kg body weight of recipient (mammal) per day and more usually
in the range of 1 to 10 mg/kg body weight per day. Thus, for a 70 kg
adult mammal, the actual amount per day would usually be from 70 to 700
mg and this amount may be given in a single dose per day or more usually
in a number (such as two, three, four, five or six) of sub-doses per day
such that the total daily dose is the same. An effective amount of a salt
or solvate, or physiologically functional derivative thereof, may be
determined as a proportion of the effective amount of the compound of
formula (I) per se. It is envisaged that similar dosages would be
appropriate for treatment of the other conditions referred to above.

[0144]The compounds of this invention may be made by a variety of methods,
including standard chemistry. Any previously defined variable will
continue to have the previously defined meaning unless otherwise
indicated. Illustrative general synthetic methods are set out below and
then specific compounds of the invention are prepared in the Working
Examples.

[0145]Compounds of general formula (I) may be prepared by methods known in
the art of organic synthesis as set forth in part by the following
synthesis schemes. In all of the schemes described below, it is well
understood that protecting groups for sensitive or reactive groups are
employed where necessary in accordance with general principles of
chemistry. Protecting groups are manipulated according to standard
methods of organic synthesis (T. W. Green and P. G. M. Wuts (1991)
Protecting Groups in Organic Synthesis, John Wiley & Sons). These groups
are removed at a convenient stage of the compound synthesis using methods
that are readily apparent to those skilled in the art. The selection of
processes as well as the reaction conditions and order of their execution
shall be consistent with the preparation of compounds of Formula (I).

[0146]Compounds of general formula (I) can be prepared according to the
synthetic sequences illustrated in Schemes 1-6 and further detailed in
the Examples section following.

##STR00019##

[0147]As illustrated in Scheme 1, compounds of general formula (I) may be
synthesized starting with compound A,
ethyl-3-aminopyrazine-2-carboxylate. A can be converted by reduction
using an appropriate reagent, such as DIBALH or LAH, to either aldehyde B
or alcohol C. One way these intermediates A and B can be converted to
intermediate D is by condensation with a substituted phenylenediamine or
heterocyclic ortho dianiline (for example intermediates 0 and R in scheme
5 below) in an appropriate solvent at temperatures between 30 and
250° C., often in the presence of an appropriate additive. For
example, heating aldehyde B or alcohol C, appropriate substituted or
heterocyclic phenylenediamine 0 or R and NaHSO3 in dimethylacetamide
at 200° C. in a microwave for 10 minutes provides compounds of
formula D.

[0148]Compounds of formula E may be synthesized by reaction of compounds D
with a suitable brominating agent in a suitable solvent. There are a
variety of conditions known in the chemical literature that are useful
for halogenating an aromatic ring. For example, one can utilize
N-bromosuccinimide in THF.

[0149]Compounds of general formula (I) can be synthesized from compounds
of general formula E through a variety of metal mediated coupling
reactions well known to those skilled in the art. For example, reaction
of aryl halides such as E with an aryl tin species or an aryl boronic
acid species can be carried out in an appropriate solvent in the presence
of an appropriate catalyst and an appropriate base at a temperature
between 30° C. and 250° C. These reactions (Suzuki reaction
with an aryl boronic acid and Stille reaction with an aryl tin reagent)
are well described in the literature, and a number of catalyst, base,
solvent, and temperature combinations have proven useful. For example,
heating an appropriate compound of general formula E with an aryl boronic
acid, aqueous sodium carbonate and dichlorobis(triphenylphosphine)
palladium (II) in dimethoxyethane at 150° C. for 10 minutes in a
SmithSynthesizer microwave is one method useful for synthesis of products
of general formula (I). Other well described reactions such as the Heck
reaction, Sonogashira reaction, carbonylation reactions and cyanation
reactions may be used to generate other compounds of general formula (I)
that replace the bromine of compounds E with different functionality,
such as substituted olefins, substituted acetylenes, substituted amides,
a carboxylic acid, or nitrile. Like the Suzuki and Stille reactions, a
number of catalyst, base, solvent, and temperature combinations have
proven useful to carry out the Sonogashira reactions, Heck reactions,
carbonylation reactions, and cyanations.

##STR00020##

[0150]Compounds of general formula (I) may also be synthesized as depicted
in scheme 2. Compound of formula F may be synthesized by reaction of
compound A, ethyl-3-aminopyrazine-2-carboxylate, with a suitable
brominating agent in a suitable solvent. There are a variety of
conditions known in the chemical literature that are useful for
halogenating an aromatic ring. For example, one can utilize
N-bromosuccinimide in THF. Compounds of general formula G can be
synthesized by a variety of metal mediated coupling reactions that are
well-described in the literature and known to one skilled in the art.
These include, but are not limited to, Heck reactions, Suzuki reactions,
Stille reactions, Sonogashira reactions, carbonylation reactions, and
cyanation reactions. For all of these types of reactions, a number of
catalyst, base, solvent, and temperature combinations have been explored
and have proven useful for carrying out the desired transformation.
Compounds of general formula (I) may be synthesized from compounds of
general formula G by reaction with a substituted phenylenediamine or
heterocyclic ortho dianiline (for example intermediates O and R in scheme
5 below) in an appropriate solvent at temperatures between 30 and
250° C., often in the presence of an appropriate additive. For
example, reaction of a compound of general formula G, an appropriate
substituted or heterocyclic phenylenediamine O or R, diethyl
cyanophosphonate, and triethylamine in dimethoxyethane as solvent at
200° C. for 10 min in the SmithSynthesizer microwave affords
compounds of general formula (I).

##STR00021##

[0151]Scheme 3 depicts an alternate way to synthesize compounds of general
formula (I). Compound H can be synthesized by reaction of compound B with
a suitable brominating agent in a suitable solvent at a suitable
temperature. There are a variety of conditions known in the chemical
literature that are useful for halogenating an aromatic ring. For
example, one can utilize N-bromosuccinimide in THF. Compound H can then
be subjected to a variety of coupling reactions that are well-described
in the literature and known to one skilled in the art. These include, but
are not limited to, Heck reactions, Suzuki reactions, Stille reactions,
Sonogashira reactions, carbonylation reactions, and cyanation reactions.
For all of these types of reactions, a number of catalyst, base, solvent,
and temperature combinations have been explored and have proven useful
for carrying out the desired transformation. Application of these sorts
of conditions, as described above and further illustrated in the detailed
examples following, give compounds of general formula J. Compound of
general formula J can be converted into compounds of general formula (I)
by condensation with a substituted phenylenediamine or heterocyclic ortho
dianiline (for example intermediates 0 and R in scheme 5 below) in an
appropriate solvent at temperatures between 30 and 250° C., often
in the presence of an appropriate additive.

[0152]Intermediates used in schemes 1, 2, and 3 can be obtained from
commercial sources or synthesized by one skilled in the art. Some of the
intermediates may be synthesized, for example, by the synthetic sequences
outlined in schemes 4, 5, and 6, and further detailed in the experimental
sections following.

##STR00022##

[0153]Scheme 4 illustrates the alkylation of a benzimidazole with an
appropriate R3 group. This transformation can be carried out by reaction
of a compound such as K, in an appropriate solvent, with a suitable base
and an appropriate alkylating agent, at a suitable temperature. For
example, reaction of K with 2-bromoethyl methyl ether and cesium
carbonate in DMF as solvent at ambient temperature gives a compound L
with R3 being a methoxy ethyl moiety. There are a wide variety of
alkylating agents commercially available, and they are also readily
synthesized by one skilled in the art. Scheme 4 illustrates alkylation of
the benzimidazole ring in particular. As noted previously, the "D" group
of general formula (I) may include not only substituted benzimidazoles,
but other heterocyclic systems as well. One skilled in the art will
recognize that these other systems may be alkylated to incorporate an R3
group in a similar manner as to that depicted in scheme 4 for the
benzimidazole case.

##STR00023##

[0154]Substituted ortho-phenylene diamines and heterocyclic
ortho-di-anilines are used in the transformations described in schemes 1,
2, and 3. Some of these are commercially available. Others may be
synthesized by known methods, including the method depicted in scheme 5.
In this scheme, molecules of general structure 0 and R are prepared by
reduction of the nitro group of compounds of general formula N and Q.
Nitro groups may be reduced by a variety of methods, including
hydrogenation in an appropriate solvent in the presence of an appropriate
catalyst such as Palladium on Carbon, or with tin (II) chloride in an
appropriate solvent. Other methods for nitro reduction can be found in
the book Comprehensive Organic Transformations by Richard LaRock.
Compounds of general formula N and Q can be synthesized by reaction of an
appropriate substituted amine (R3-NH2) with compounds such as M and P.
"LG" in the general structures M and P stands for "leaving group" and
represents, for example, fluoro, chloro, bromo, or methoxy, or other
groups that can be displaced by a nucleophile at an appropriate
temperature in an appropriate solvent.

##STR00024##

[0155]In some instances, the chemistry depicted in schemes 1, 2, and 3
that describe the synthesis of compounds of general formula (I) make use
of boronic acids or boronate esters. Many boronic acids and boronate
esters are commercially available. When not commercially available,
boronic acids and boronate esters may be synthesized by standard methods,
including those depicted in scheme 6. Heteroaryl or aryl boronate esters
may be synthesized by reaction of an aryl or heteroaryl halide with
bis(pinacolato)diboron and an appropriate palladium catalyst in an
appropriate solvent with appropriate additives. For example, reaction of
an aryl halide and bis(pinacolato)diboron with PdCl2(dppf)2,
and potassium acetate, in DMF as solvent at 80° C. for 90 minutes
can give boronate esters of general formula R. Heteroaryl or aryl boronic
acids may be synthesized by treating an appropriate aryl halide or
heteroaryl halide with a strong base such as n-BuLi or t-BuLi in a
solvent such as THF or dioxane, followed by reaction of the intermediate
organometallic species with a reagent to introduce the boron. For
example, reaction of an aryl halide in THF at -70° C. with n-butyl
lithium, followed by addition of tri-isopropylborate gives, after
standard work up, aryl boronic acids of general formula T.

[0156]Certain embodiments of the present invention will now be illustrated
by way of example only. The physical data given for the compounds
exemplified is consistent with the assigned structure of those compounds.

EXAMPLES

[0157]As used herein the symbols and conventions used in these processes,
schemes and examples are consistent with those used in the contemporary
scientific literature, for example, the Journal of the American Chemical
Society or the Journal of Biological Chemistry. Standard single-letter or
three-letter abbreviations are generally used to designate amino acid
residues, which are assumed to be in the L-configuration unless otherwise
noted. Unless otherwise noted, all starting materials were obtained from
commercial suppliers and used without further purification. Specifically,
the following abbreviations may be used in the examples and throughout
the specification:

[0158]All references to ether are to diethyl ether; brine refers to a
saturated aqueous solution of NaCl. Unless otherwise indicated, all
temperatures are expressed in ° C. (degrees Centigrade). All
reactions are conducted under an inert atmosphere at room temperature
unless otherwise noted.

1H NMR spectra were recorded on a Varian VXR-300, a Varian Unity-300,
a Varian Unity-400 instrument, a Brucker AVANCE-400, or a General
Electric QE-300. Chemical shifts are expressed in parts per million (ppm,
6 units). Coupling constants are in units of Hertz (Hz). Splitting
patterns describe apparent multiplicities and are designated as s
(singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m
(multiplet), br (broad).

[0161]Low-resolution mass spectra (MS) were recorded on a JOEL
JMS-AX505HA, JOEL SX-102, or a SCIEX-APIiii spectrometer; LC-MS were
recorded on a micromass 2MD and Waters 2690; high resolution MS were
obtained using a JOEL SX-102A spectrometer. All mass spectra were taken
under electrospray ionization (ESI), chemical ionization (CI), electron
impact (EI) or by fast atom bombardment (FAB) methods. Infrared (IR)
spectra were obtained on a Nicolet 510 FT-IR spectrometer using a 1-mm
NaCl cell. Most of the reactions were monitored by thin-layer
chromatography on 0.25 mm E. Merck silica gel plates (60F-254),
visualized with UV light, 5% ethanolic phosphomolybdic acid or
p-anisaldehyde solution. Flash column chromatography was performed on
silica gel (230-400 mesh, Merck).

Example 1

3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine

##STR00025##

[0162](a) Preparation of Ethyl-(3-nitropyridin-4-yl)amine

##STR00026##

[0164]4-Methoxy-3-nitropyridine hydrochloride (11.2 g, 58.9 mmol) in
ethanol (75 ml) was treated with a 70% solution of ethylamine in water
(64 ml) and heated under reflux for 2 hours. After cooling to room
temperature, the solvent was removed in vacuo and the residue dissolved
in ethyl acetate and water. The mixture was extracted (×3) with
ethyl acetate, washed with water and saturated aqueous sodium chloride
solution before drying over magnesium sulfate. Evaporation of the solvent
afforded the title compound (11.7 g, 96%).

[0167]Ethyl-(3-nitropyridin-4-yl)amine (8.7 g, 52.0 mmol) in ethanol (150
ml) was hydrogenated for 18 hours in the presence of 10% palladium on
carbon. After filtration of the catalyst through celite, the filtrate was
concentrated in vacuo to afford the title compound (6.7 g, 94%).

[0170]Methyl-3-aminopyrazine-2-carboxylate (11 g) was dissolved in THF and
cooled to -78° C. Diisobutylaluminum hydride (1M in hexanes, 250
mL) was added, and the reaction stirred at -78° C. for 4 hours.
The reaction was then warmed to 0° C. for one hour before being
quenched slowly by addition of 1M hydrochloric acid. Ethyl acetate was
added and the layers separated. The organic layer was dried over
magnesium sulfate, filtered and concentrated. The residue was triturated
in hexanes to afford title compound (3.0 g, 34%).

[0173]3-aminopyrazine-2-carbaldehyde (made in example 1(c)) (0.30 g, 2.4
mmol), N4-ethylpyridine-3,4-diamine (made in example 1(b)) (0.36 g,
2.6 mmol), and sodium hydrogensulfite (0.30 g) were combined in 3 mL of
dimethylacetamide and heated to 200° C. in a SmithSynthesizer
microwave for 10 minutes. The reaction mixture was partitioned between
ethyl acetate and water. The reaction was extracted with ethyl acetate
(×3), and the combined organic layers were washed with water and
saturated aqueous sodium chloride solution, and dried over magnesium
sulfate. After filtration, the organics were concentrated in vacuo.
Trituration with diethyl ether affords the title compound as tan solids
(0.46 g, 80%).

[0176]Methyl-3-aminopyrazine-2-carboxylate (14.22 g, 93 mmol) was
suspended in tetrahydrofuran (1 L) and cooled under a nitrogen atmosphere
in a methanol/ice bath. Lithium aluminium hydride (100 ml, 1M solution in
diethyl ether, 100 mmol) was added at such a rate to maintain the
temperature between 8-10° C. Once addition was complete the
reaction was stirred at room temperature for 3 hours and then heated at
reflux for 20 minutes. The reaction was then cooled to 0° C. and
quenched with water (30 mL in 100 mL tetrahydrofuran) keeping the
temperature below 8° C. The reaction was then stirred at room
temperature for 30 minutes and then filtered. The residue was washed with
hot ethyl acetate (250 mL×2) filtered. The two filtrates were
combined and evaporated to dryness. This produced
(3-amino-pyrazin-2-yl)-methanol (7.38 g) as a pale orange solid.

[0210]3-(1H-benzimidazol-2-yl)pyrazin-2-amine (0.302 g, 0.14 mmol) was
dissolved in N,N-dimethyl formamide (10 mL) and treated with 2-bromoethyl
methyl ether (0.15 mL, 0.16 mmol) and cesium carbonate (0.475 g, 1.4
mmol). The mixture was stirred at ambient temperature for 20 hours and
then filtered through celite. The filtrate was concentrated and
partitioned between ethyl acetate and water. The mixture was extracted
into ethyl acetate (×3) and the combined organic layers were washed
with water, and then with saturated sodium chloride. The organics were
dried over magnesium sulfate, filtered and concentrated. Trituration with
diethyl ether afforded the title compound as tan solids (0.275 g, 0.10
mmol).

[0221]Methyl 2-aminopyrazine-3-carboxylate (5.0 g, 32.65 mmol) was
dissolved in 100 mL of THF and treated with N-Bromosuccinimide (6.9 g,
39.18 mmol) all at once. The mixture was stirred at room temperature for
1.5 hrs, and then another 0.5 equivalents of N-bromosuccinimide was added
and stirring continued for 1 hr. 10 grams of sodium sulfate were added,
the mixture was vigorously stirred for 15 minutes, and the solvent was
removed in vacuo. The residue obtained was suspended in 250 mL of water
and stirred rapidly. Filtration afforded the title compound, methyl
3-amino-6-bromopyrazine-2-carboxylate, as a tan solid (6.33 g).

[0224]Methyl 3-amino-6-bromopyrazine-2-carboxylate (0.116 g, 0.5 mmol),
3-fluorophenylboronic acid (0.14 g, 1.0 mmol),
dichlorobis(triphenylphosphine)palladium(II) (0.018 g, 0.02 mmol), and
K2CO3 (0.14 g, 1.0 mmol) were combined in 3 mL of 4:1
CH3CN:H2O and heated to 150° C. for 10 minutes in the
SmithSynthesizer microwave. Upon cooling, the reaction mixture was
diluted with MeOH and H2O to dissolve all but the catalyst. The
mixture was filtered and the pH was adjusted to 6 with 2N HCl. The
solution was concentrated in vacuo, and the solids were collected to
afford 3-amino-6-(3-fluorophenyl)pyrazine-2-carboxylic acid (96 mg) as a
yellow solid.

[0239]N,N-dimethyl-4-bromobenzenesulfonamide (8.0 g, 30.3 mmol) was
dissolved in dry tetrahydrofuran (40 mL) and stirred at -70° C.
under a nitrogen atmosphere. n-Butyllithium (1.6 M in hexanes, 19 mL,
30.4 mmol) was carefully added keeping temp. <-65° C. and the
mixture stirred for 30 min. The reaction mixture was transferred by
cannula to a solution of tri-isopropylborate (14 mL, 60.7 mmol) in dry
tetrahydrofuran (40 mL) stirring at -70° C. under a nitrogen
blanket for an hour. The mixture was warmed to room temperature over a
further hour. 2M hydrochloric acid (50 mL) was added and the mixture
stirred for 80 min. The aqueous layer was extracted with ethyl acetate
and the organic layers combined washed with brine and dried over sodium
sulfate. Concentration in vacuo gave an oily semi-solid (7.9 g). The
crude product was re-crystallised from ethylacetate/cyclohexane and
collected by vacuum filtration to afford 2.5 g of
4-dimethylaminosulphonylphenylboronic acid.

[0241]5-bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine
(0.032 g, 0.10 mmol) (made in example 2),
4-dimethylaminosulphonylphenylboronic acid (0.046 g, 0.20 mmol),
Pd(PPh3)2Cl2 (0.0035 g, 0.005 mmol) and K2CO3
(0.050 g, 0.36 mmol) were combined in 0.5 mL of N,N-dimethylformamide and
heated to 200° C. in the SmithSynthesizer microwave for 8 minutes
and then for a further 8 minutes at 250° C. The reaction mixture
was concentrated in vacuo and the residue purified by HPLC to give 0.0079
g of the title compound.

[0255]5-bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine
(0.032 g, 0.10 mmol) (made in example 2),
tert-butyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)phenoxy]acetate
(0.067 g, 0.20 mmol), Pd(PPh3)2Cl2 (0.0035 g, 0.005 mmol)
and K2CO3 (0.050 g, 0.36 mmol) were combined in 0.5 mL of
N,N-dimethylformamide and heated to 200° C. in the
SmithSynthesizer microwave for 8 minutes and then for a further 8 minutes
at 250° C. The reaction mixture was concentrated in vacuo and the
residue purified by mass directed HPLC to give 0.0038 g of the title
compound.

[0264]5-bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine
(0.032 g, 0.10 mmol) (made in example 2),
tert-butyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)phenoxy]acetate
(0.067 g, 0.20 mmol), Pd(PPh3)2Cl2 (0.0035 g, 0.005 mmol)
and K2CO3 (0.050 g, 0.36 mmol) were combined in 0.5 mL of
N,N-dimethylformamide and heated to 200° C. in the
SmithSynthesizer microwave for 8 minutes and then for a further 8 minutes
at 250° C. The reaction mixture was concentrated in vacuo and the
residue purified by mass directed HPLC to give 0.0048 g of the title
compound.

[0279]5-bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine
(0.032 g, 0.10 mmol) (made in example 2), 4-boronobenzoic acid (0.033 g,
0.20 mmol), Pd(PPh3)2Cl2 (0.0035 g, 0.005 mmol) and
K2CO3 (0.050 g, 0.36 mmol) were combined in 0.5 mL of
N,N-dimethylformamide and heated to 200° C. in the
SmithSynthesizer microwave for 8 minutes and then for a further 8 minutes
at 250° C. The reaction mixture was concentrated in vacuo and the
residue purified by mass directed HPLC to give 0.0032 g of the title
compound.

[0282]5-bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine
(0.032 g, 0.10 mmol) (made in example 2),
3-((tert-butoxycarbonyl)aminomethyl)phenylboronic acid (0.050 g, 0.20
mmol), Pd(PPh3)2Cl2 (0.0035 g, 0.005 mmol) and
K2CO3 (0.050 g, 0.36 mmol) were combined in 0.5 mL of
N,N-dimethylformamide and heated to 200° C. in the
SmithSynthesizer microwave for 8 minutes and then for a further 8 minutes
at 250° C. The reaction mixture was concentrated in vacuo and the
residue purified by HPLC to give 0.0037 g of the title compound.

[0294]For IC50 determination, test compounds were typically dissolved at
10 mM in 100% DMSO, with subsequent serial dilution into 10% DMSO.
Compounds were typically assayed over an eleven point dilution range with
a concentration in the assay of 10 uM to 3 nM, in duplicate. IC50 values
were calculated by bespoke curve fitting software and then converted to
pIC50.

[0296]Streptavidin PVT SPA beads were added to a concentration of 0.4 mg
per well. The plates were shaken for 10 minutes before centrifugation at
2500 rpm for 10 minutes. P33 incorporation was quantified by
scintillation counting in a Wallac Trilux.

[0297]All exemplified Examples 1-26 were run with the recited assay and
showed inhibitory activity versus Rock-1 with a pIC50 of 5.0 or
greater.